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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Agonists of dopamine receptors can lower blood pressure by vasodilation through action on dopamine1 receptors, inhibition of sympathetic nerve activity by action on dopamine2 receptors, or actions in the central nervous system. Fenoldopam, a selective dopamine1 agonist, piribedil, a selective dopamine2 agonist, and dipropyl dopamine, a mixed dopamine1 and dopamine2 agonist, were injected intravenously in pentobarbital-anesthetized, spontaneously hypertensive rats (SHR). The mechanism for the antihypertensive effect was evaluated by administration of the selective dopamine1 antagonist SCH 23390 and the selective dopamine2 antagonist domperidone. While SCH 23390 only antagonized the hypotensive effects of fenoldopam, domperidone abolished the fall in blood pressure produced by dipropyl dopamine and piribedil but not by fenoldopam. Increments in heart rate and plasma norepinephrine levels accompanied the hypotensive effects of fenoldopam. The increase in heart rate was abolished by a dose of SCH 23390 sufficient to completely block the hypotensive effects and was significantly attenuated by the ganglionic blocking agent hexamethonium, which suggests that the increase in heart rate was due to a baroreceptor reflex. Fenoldopam does not cross the blood-brain barrier, which suggests that its hypotensive effect was mediated by peripheral dopamine1 receptors. Since domperidone does not cross the blood-brain barrier and significantly antagonized the hypotensive and bradycardic effects of dipropyl dopamine and piribedil, these effects were mediated primarily by peripheral dopamine2 receptors. These results indicate that SCH 23390 and domperidone are useful agents to identify the receptor subtype mediating the action of dopamine agonists in SHR.
Hypertension 1986 Apr
PMID:Selective antagonism of the hypotensive effects of dopamine agonists in spontaneously hypertensive rats. 287 24

The dopamine beta-hydroxylase inhibitor SK&F 102698 was characterized by studying its cardiovascular effects in hypertensive rats. The antihypertensive effects of SK&F 102698 (50 mg/kg p.o.) were studied in three different rat models of hypertension. In spontaneously hypertensive and deoxycorticosterone acetate-salt rats SK&F 102698 produced blood pressure reductions of approximately 21 and 23%, respectively. In contrast, SK&F 102698 did not produce a significant decrease in blood pressure in 2-kidney, 1-clip Goldblatt hypertensive rats. The antihypertensive mechanism of action of dopamine beta-hydroxylase inhibition was probed with the selective DA1-receptor antagonist SCH 23390, which produced an attenuation of the antihypertensive effects of SK&F 102698. Experiments were designed to separate the peripheral from the central components of the cardiovascular effects of SK&F 102698. In spinal cord stimulated pithed spontaneously hypertensive rats, SK&F 102698 reduced blood pressure but not heart rate, indicating a peripherally mediated vasodilation and a centrally mediated heart rate effect. Furthermore, when SK&F 102698 was administered directly into the fourth ventricle of conscious spontaneously hypertensive rats, a pronounced bradycardia and lowering of blood pressure was observed. SCH 23390 (200 micrograms/kg i.v.) and l-sulpiride (1 mg/kg i.v.) inhibited the cardiovascular effects of SK&F 102698 administered into the fourth ventricle. These data indicate that inhibition of dopamine beta-hydroxylase with SK&F 102698 results in both peripherally and centrally mediated cardiovascular effects and suggest that central dopamine receptors contribute to the control of systemic blood pressure in hypertensive models associated with an increased sympathetic outflow.
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PMID:Further characterization of the cardiovascular effects of the dopamine beta-hydroxylase inhibitor SK&F 102698 in conscious hypertensive rats. 305 29

Intravenous (i.v.) infusions of SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol) produced dose-related antagonism of dopamine (DA)-induced renal vasodilation in phenoxybenzamine-treated dogs at infusion rates of 0.05, 0.15, and 0.5 microgram/kg/min. The highest rate of infusion, 0.5 microgram/kg/min, resulted in pronounced antagonism of this DA1-receptor-mediated response. In contrast, a 10 times higher infusion rate, 5 micrograms/kg/min, did not antagonize the following DA2-mediated responses: increase in femoral blood flow produced by apomorphine and piribedil in untreated dogs; and N,N-di-n-propyl DA (DPDA)-induced inhibition of the tachycardia produced by cardiac accelerator nerve stimulation. Infusions of 0.5 micrograms/kg/min or greater of SCH 23390 did not affect the actions of agonists of alpha1-, alpha2-, beta1-, and beta2-adrenergic, histamine, serotonin, and cholinergic receptors, or the vasodilation produced by bradykinin. At the infusion rates used in these studies, SCH 23390 did not affect arterial blood pressure or heart rate. These data indicate that SCH 23390 is the most specific and selective antagonist of DA1 receptors thus far described. Accordingly, SCH 23390 should be extremely useful in investigations of potential physiological and pathological roles of DA and in the classification of DA receptors.
Hypertension
PMID:Separation of peripheral dopamine receptors by a selective DA1 antagonist, SCH 23390. 614 34

SCH 31846, 1-(N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanyl)-cis, syn-octahydro-(H-indole-2-S)-carboxylic acid; CI-907; PD 109, 763-2, is a new non-sulfhydryl-containing, angiotensin-converting enzyme (ACE) inhibitor. The present investigation describes its ACE inhibitory properties and compares them to those of MK 421. The diacid of SCH 31846 inhibited rabbit pulmonary ACE with an IC50 of 2.2 nM (MK 421 diacid 2.5 nM). The drug behaved as a competitive and specific inhibitor in vitro. SCH 31846 and its diacid effectively inhibited pressor actions of intravenous injection of angiotensin I (AI) in anesthetized rats. ID50 values were 27 and 11 micrograms/kg for SCH 31846 and SCH 31846 diacid, respectively (MK 421 and MK 421 diacid 57 and 15 micrograms/kg, respectively). Oral administration of SCH 31846 (0.03-1 mg/kg) inhibited pressor actions of AI in conscious rats with a duration of over 16 h at 0.3 and 1 mg/kg. SCH 31846 was 2.2 times as potent as MK 421 in this regard. The diacid of SCH 31846 was considerably less potent than the ester, implying poor oral absorption of the former. Effective ACE inhibition, as judged by attenuation of pressor actions of AI, was noted in dogs after both intravenous and oral administrations of SCH 31846. Onset of action was more rapid than that of MK 421. Intravenous administration of SCH 31846 inhibited the renal vascular actions of intrarenal injection of AI, indicating effective blockade of the renal enzyme. Intracerebroventricular administration of SCH 31846 diacid blocked pressor responses to intracerebroventricular AI, whereas oral administration of SCH 31846 (10 mg/kg) did not, implying that SCH 31846 inhibits brain ACE but does not gain access to the cerebral enzyme when administered orally. These data indicate that SCH 31846 is a potent and specific non-sulfhydryl ACE inhibitor. As such, it should be useful in the treatment of hypertension and heart failure.
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PMID:Angiotensin-converting enzyme inhibitory activity of SCH 31846, a new non-sulfhydryl inhibitor. 619 64

Blockade of atrial natriuretic factor (ANF) degradation by specific neutral endopeptidase (NEP) inhibitors may be useful in treatment of hypertension because of the potential diuretic, natriuretic, and arterial pressure (AP)-lowering effects. To test this possibility, we examined the effects of chronic oral treatment with the NEP inhibitor SCH 42495 on BP, diuresis, natriuresis, plasma ANF, cyclic GMP, and the renin-angiotensin system (RAS) in conscious unrestrained spontaneously hypertensive rats (SHR) and compared them with the effects induced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPIR). Four groups of adult SHR were treated orally for 4 weeks with placebo, SCH 42495 3 mg/kg twice daily (b.i.d.), SCH 42495 30 mg/kg b.i.d., and spirapril 1 mg/kg b.i.d. Systolic BP (SBP) was measured weekly, and 24-h urine was collected every week for measurement of urinary volume, sodium, potassium, and cyclic GMP excretion. Plasma ANF, cyclic GMP, renin activity (PRA), and aldosterone (ALDO) were determined from blood collected when the rats were killed. After 4-week treatment with SCH 42495, circulating levels of ANF were similar in both SCH 42495- and placebo-treated SHR; plasma cyclic GMP was higher, however, in the treated rats than in controls and urinary cyclic GMP increased only with the higher dose of SCH 42495. PRA and plasma ALDO tended to be lower in both SCH 42495-treated groups than in controls, yet BP, diuresis, and natriuresis throughout the study were not different from controls. In contrast, spirapril decreased BP; this effect was associated with significant increments in renin and decrements in ALDO and ANF, without changes in plasma and urinary cyclic GMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic and humoral effects of chronic treatment with the neutral endopeptidase inhibitor SCH 42495 in spontaneously hypertensive rats. 752 51

To assess the efficacy of neutral endopeptidase 24.11 inhibition in the setting of elevated plasma levels of angiotensin II (Ang II), we studied the hemodynamic, renal, and hormonal effects of bolus injections of the potent and specific neutral endopeptidase inhibitor SCH 39370 or vehicle (control) in 10 sheep with Ang II-induced hypertension. Ang II infusion (5 ng/kg per minute for 6 days) sufficient to increase plasma Ang II levels 50% to 100% induced a consistent rise in mean arterial pressure (mean increment, 15 mm Hg; P < .0001) and increased plasma atrial natriuretic peptide (P = .017) and its second messenger cGMP (P = .049). Compared with time-matched control observations after vehicle alone, SCH 39370 (2.5 mg/kg) further increased plasma atrial natriuretic peptide (P = .0006), cGMP (P = .006), and plasma Ang II (P = .054). Systolic and mean arterial pressures tended to fall after SCH 39370, but these changes were not significant compared with control. No significant changes were observed in urinary volume and sodium excretion. Viewed in relation to previous studies in normotensive sheep, the current findings indicate that the vasodepressor response to neutral endopeptidase inhibition is blunted in hyperangiotensinemic sheep, in which neutral endopeptidase inhibition further augments plasma Ang II levels.
Hypertension 1995 Jul
PMID:Endopeptidase inhibition in angiotensin-induced hypertension. Effect of SCH 39370 in sheep. 760 38

To determine the effects of intravenous administration of dopamine hydrochloride (DA) on tumor blood flow (TBF), we measured the blood flow of normal subcutaneous tissue and subcutaneous tumor (LY-80, a variant of Yoshida sarcoma) in enflurane-anesthetized male Donryu rats using a hydrogen clearance method. Measurements were made before and during intravenous infusion of DA at a rate of 5 micrograms/kg/min, while recording the mean arterial blood pressure of the rats. Under mild hypertension induced by DA, the blood flow of normal subcutis decreased and TBF increased significantly. SCH-23390, an antagonist of the DA1 receptor, inhibited the enhancement of TBF by DA; while domperidone, an antagonist of the DA2 receptor, did not modify the effects of DA. In experimental chemotherapy against the tumor using adriamycin (ADM) 5 mg/kg i.v., only the combination of DA and ADM significantly inhibited the tumor growth. Moreover, DA reduced the weight loss caused by ADM. These results indicate that DA could have a role in increasing TBF and possibly enhance drug delivery to tumors. Moreover, it appears that the DA1 receptor contributes, at least in part, to the enhanced blood flow in rat subcutaneous tumor following DA administration.
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PMID:Effects of intravenous infusion of dopamine on tumor blood flow in rat subcutis. 801 14

In the present study we have investigated, using radioligand binding techniques and the dopamine receptor antagonist [3H]SCH 23390 as a ligand, the existence of specific dopamine D1-like receptors in human peripheral blood lymphocytes. [3H]SCH 23390 binding to human peripheral blood lymphocytes was time-, temperature-, concentration-dependent and of high affinity with a dissociation constant value (Kd) of 0.58 +/- 0.05 nM and a maximum binding density (Bmax) of 11.02 +/- 0.3 fmol/5 x 10(6) cells. The binding was also reversible. Pharmacological analysis displacement curves of [3H]SCH 23390 binding with dopamine competing with the radioligand in the submicromolar range suggests that peripheral blood lymphocytes express dopamine D5 receptors rather than dopamine D1 receptors. These results, which are consistent with studies performed with molecular biology techniques, suggest that dopamine may modulate peripheral blood lymphocyte activity. Radioligand binding techniques, applied to lymphocyte receptor studies for their feasibility and flexibility may be used to investigate the possible relationship between the immune and dopaminergic systems. Moreover, they could be employed as a tool in Parkinson's disease, migraine, schizophrenia and hypertension research.
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PMID:Dopamine D5 receptors in human peripheral blood lymphocytes: a radioligand binding study. 805 Dec 91

In contrast to the wealth of information available concerning the response of plasma atrial natriuretic peptide to changes in pressure and volume status and to inhibition of endopeptidase 24.11, very little is known of possible concomitant effects on brain natriuretic peptide. The effects of change in posture, pressor infusions of angiotensin II, or inhibition of endopeptidase 24.11 were documented in two groups of patients with essential hypertension receiving one of two orally active inhibitors (SCH 42495 or UK 79300) in double-blind, placebo-controlled, random-order crossover studies. Sustained (4 days) inhibition of endopeptidase 24.11 with either inhibitor significantly enhanced plasma atrial natriuretic peptide (P < .05, both groups) but suppressed plasma brain natriuretic peptide (P < .01, both groups) in association with significant falls in arterial pressure (P < .05, both groups). Assumption of the recumbent posture increased plasma atrial natriuretic peptide (20 +/- 5 vs 13 +/- 3 pmol/L, P < .05), whereas brain natriuretic peptide was unchanged (7 +/- 0.3 vs 7 +/- 0.4 pmol/L, NS). Pressor infusions of angiotensin II increased plasma levels of both atrial natriuretic peptide and brain natriuretic peptide (33 +/- 11 vs 17 +/- 4 pmol/L, P < .05, and 7.5 +/- 0.6 vs 5.5 +/- 0.4 pmol/L, P < .05, respectively). In contrast to atrial natriuretic peptide, brain natriuretic peptide probably is primarily regulated by left ventricular load rather than by atrial distending pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Aug
PMID:Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension. 834 Jan 58

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of adult spontaneously hypertensive rats. To determine the potential consequences of this phenomenon, we performed the present studies in which renal proximal tubule suspensions obtained from spontaneously hypertensive and Wistar-Kyoto rats of 10-12 weeks of age were used. The tubule suspensions were incubated with dopamine in the presence or absence of dopamine receptor antagonists, and sodium, potassium adenosine trisphosphatase (sodium pump) activity was measured as the ouabain-sensitive adenosine trisphosphate hydrolysis. We found that dopamine produced a concentration-related inhibition of sodium pump activity in the normotensive rats but not in the hypertensive rats. Dopamine-induced inhibition of sodium pump activity in the normotensive rats was abolished by the phospholipase C inhibitor U-73122 or the protein kinase C inhibitor sphingosine, suggesting the involvement of a phospholipase C-coupled protein kinase C pathway in this response. Dopamine-induced inhibition in the normotensive rats was attenuated by the dopamine-1 receptor antagonist SCH 23390 but not by the dopamine-2 receptor antagonist domperidone. To identify possible sites of defect in dopamine-1 receptor-coupled signaling pathways in the hypertensive rats, we incubated the proximal tubules with phorbol 12,13-dibutyrate or the synthetic diacylglycerol analogue 1-oleoyl-2-acetyl-rac-glycerol. The results showed that both compounds inhibited sodium pump activity as effectively in the hypertensive as in the normotensive rats, suggesting that the protein kinase C-coupled sodium pump pathway was not defective in the hypertensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Mar
PMID:Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats. 838 2


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